U.S. patent application number 12/295381 was filed with the patent office on 2010-09-09 for benzimidazole derivatives.
Invention is credited to Marc Gerspacher, Karl Heinz Krawinkler.
Application Number | 20100227889 12/295381 |
Document ID | / |
Family ID | 36424926 |
Filed Date | 2010-09-09 |
United States Patent
Application |
20100227889 |
Kind Code |
A1 |
Gerspacher; Marc ; et
al. |
September 9, 2010 |
Benzimidazole Derivatives
Abstract
A compound of formula (I) or a pharmaceutically acceptable salt
or prodrug ester thereof: wherein R, X and Y are as disclosed in
the specification, suitable for the treatment of osteoporosis.
##STR00001##
Inventors: |
Gerspacher; Marc; (Kappel,
CH) ; Krawinkler; Karl Heinz; (Basel, CH) |
Correspondence
Address: |
NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
220 MASSACHUSETTS AVENUE
CAMBRIDGE
MA
02139
US
|
Family ID: |
36424926 |
Appl. No.: |
12/295381 |
Filed: |
March 28, 2007 |
PCT Filed: |
March 28, 2007 |
PCT NO: |
PCT/EP07/02763 |
371 Date: |
September 30, 2008 |
Current U.S.
Class: |
514/338 ;
546/273.4 |
Current CPC
Class: |
A61P 3/14 20180101; A61P
5/18 20180101; A61P 9/12 20180101; A61P 25/14 20180101; A61P 9/04
20180101; A61P 19/08 20180101; A61P 25/10 20180101; A61P 25/24
20180101; A61P 1/12 20180101; A61P 17/02 20180101; A61P 21/02
20180101; A61P 25/08 20180101; A61P 1/02 20180101; A61P 9/10
20180101; A61P 19/00 20180101; A61P 19/02 20180101; A61P 25/18
20180101; A61P 25/16 20180101; C07D 401/06 20130101; A61P 25/00
20180101; A61P 25/12 20180101; A61P 25/28 20180101; A61P 25/22
20180101; A61P 19/10 20180101; A61P 1/04 20180101 |
Class at
Publication: |
514/338 ;
546/273.4 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; C07D 401/10 20060101 C07D401/10; A61P 19/08 20060101
A61P019/08 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 30, 2006 |
GB |
0606426.5 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt
or prodrug ester thereof: ##STR00029## wherein R is halo or
optionally substituted C.sub.1-C.sub.6 alkyl; X is selected from
the group consisting of O, NH, CH.sub.2, CO, SO, SO.sub.2 or S; Y
represents a group selected from the following: optionally
substituted C.sub.1-C.sub.6 alkyl, --SR.sub.1, --S(O)R.sub.1,
--S(O).sub.2R.sub.1, --OR.sub.2, wherein R.sub.1 and R.sub.2 are
selected from optionally substituted: C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkenyl or C.sub.1-C.sub.4 alkynyl; the optional
substituent or substituents on R, R.sub.1, R.sub.2 and Y being
independently selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.6 alkyl, mono or di-C.sub.1-C.sub.6
alkylamino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.6 alkylaminocarbonyl, amino, carboxy,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6
alkynyloxy, C.sub.3-C.sub.12 cycloalkyl, C.sub.3-C.sub.18
heterocycloalkyl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, nitryl, aryl; all of which, except halogen, are
independently optionally substituted by one or more substituents,
selected from the group consisting of halogen, hydroxy,
C.sub.1-C.sub.6 alkyl, mono or di-C.sub.1-C.sub.6 alkylamino,
aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.6 alkylaminocarbonyl, amino, carboxy,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.12 cycloalkyl,
C.sub.3-C.sub.18 heterocycloalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, nitryl, aryl.
2. A compound of formula (I') or a pharmaceutically acceptable
salt, or prodrug ester thereof: ##STR00030## wherein R' is halo or
optionally substituted C.sub.1-C.sub.6 alkyl; Y' represents a group
selected from the following: C.sub.1-C.sub.6 alkyl, --SR.sub.1,
--S(O)R.sub.1, --S(O).sub.2R.sub.1, --OR.sub.2, wherein R.sub.1 and
R.sub.2 are selected from optionally substituted: C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkenyl or C.sub.1-C.sub.4 alkynyl; the
optional substituent or substituents on R, R.sub.1 and R.sub.2 are
independently selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.6 alkyl, mono or di-C.sub.1-C.sub.6
alkylamino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.6 alkylaminocarbonyl, amino, carboxy,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.12 cycloalkyl,
C.sub.3-C.sub.18 heterocycloalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, nitryl, aryl; all of which, except
halogen, are independently optionally substituted by one or more
substituents, selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.6 alkyl, mono or di-C.sub.1-C.sub.6
alkylamino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.6 alkylaminocarbonyl, amino, carboxy,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.12 cycloalkyl,
C.sub.3-C.sub.18 heterocycloalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, nitryl, aryl.
3. A compound according to claim 1 wherein X is CH.sub.2 or O.
4. A compound according to claim 1 wherein Y is selected from
--SR.sub.1, --S(O)R.sub.1, --S(O).sub.2R.sub.1 and --OR.sub.2,
4. A compound according to claim 1 wherein Y is selected from
--SR.sub.1, --S(O)R.sub.1, --S(O).sub.2R.sub.1 and --OR.sub.2 and
R.sub.1 or R.sub.2 is methyl.
5. A compound according to claim 1 wherein R is halo or
trifluoromethyl.
6. A compound according to claim 1, selected from:
4-Bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methyls-
ulfanyl-pyridin-3-ylmethyl)-1H-benzoimidazole,
2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methylsulfanyl--
pyridin-3-ylmethyl)-4-trifluoromethyl-1H-benzoimidazole,
4-Bromo-2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-pyridin-3-ylmethyl)-7-
-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole,
2-(4-Isopropyl-phenyl)-5-(2-methanesulfinyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole,
2-(4-Isopropyl-phenyl)-5-(2-methanesulfonyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole,
2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methoxy-pyridin-
-3-ylmethyl)-4-trifluoromethyl-1H-benzoimidazole,
5-(2-Ethoxy-pyridin-3-ylmethyl)-2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-met-
hoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole,
5-(2-Isopropoxy-pyridin-3-yl-methyl)-2-(4-Isopropyl-phenyl)-7-methoxy-1-(-
2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole,
2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-prop-2-ynyloxy--
pyridin-3-ylmethyl)-4-trifluoromethyl-1H-benzoimidazole,
2-(4-Isopropyl-phenyl)-7-methoxy-5-[2-(2-methoxy-ethoxy)-pyridin-3-ylmeth-
yl]-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole, and
(2-{3-[2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trifluorome-
thyl-1H-benzoimidazole-5-ylmethyl]-pyridin-2-yloxy}-ethyl)-dimethylamine.
7. A pharmaceutical composition comprising a compound of formula
(I) as defined in claim 1 in association with a pharmaceutically
acceptable excipient, diluent or carrier.
8. A pharmaceutical composition according to claim 7 containing
0.03 to 300 mg of the compound of formula (I).
9. A compound of formula (I) as defined in claim 1 for promoting
the release of parathyroid hormone.
10. A method for preventing or treating bone conditions which are
associated with increased calcium depletion or resorption or in
which stimulation of bone formation and calcium fixation in the
bone is desirable in which an effective amount of a compound of
formula (I) as defined in claim 1, or a pharmaceutically-acceptable
and -cleavable ester, or acid addition salt thereof is administered
to a patient in need of such treatment.
11. A process for the preparation of a compound of formula (I) in
free or salt form as defined in claim 1, comprising: (a) for
compounds of formula (I) wherein R is optionally substituted
C.sub.1-C.sub.6 alkyl, introducing the optionally substituted
C.sub.1-C.sub.6 alkyl by reaction of a compound of formula (XV)
with a suitable organometallic reagent: ##STR00031## (b) for
compounds of formula (I) wherein R is halo, halogenation of a
compound of formula (X) using a suitable halogenating agent:
##STR00032## (c) for compounds of formula (I) wherein Y is
--SR.sub.1, reduction of a compound of formula (XI) using a
suitable reducing agent: ##STR00033## (d) for compounds wherein Y
is --S(O)R.sub.1 or --S(O).sub.2R.sub.1, by oxidation of a compound
of formula (XII): ##STR00034## (e) for compounds wherein Y is
--OR.sub.2, or --SR.sub.1 by ipso-substitution in the pyridine ring
of a compound of formula (XIII): ##STR00035## using a suitable
nucleophiles such as R.sub.2O.sup.- or R.sub.1S.sup.-.
12. Use of a compound of formula (I) in the manufacture of a
medicament for preventing or treating bone conditions which are
associated with increased calcium depletion or resorption or in
which stimulation of bone formation and calcium fixation in the
bone is desirable.
13. A pharmaceutical composition comprising a compound of formula
(I) and an additional active agent selected from: a calcitonin or
an analogue or derivative thereof, a steroid hormone, a SERM
(Selective Estrogen Receptor Modulator), vitamin D or an analog
thereof, a bisphosphonate, an RNKL inhibitor, PTH, a PTH fragment
or a PTH derivative, or a cathepsin K inhibitor for simultaneous,
separate or sequential use.
Description
[0001] The present invention relates to bicyclic compounds, in
particular to benzimidazole derivatives and to pharmaceutical uses
thereof.
[0002] Accordingly the invention provides compounds of formula (I)
or a pharmaceutically acceptable salt or prodrug ester thereof:
##STR00002##
wherein R is halo or optionally substituted C.sub.1-C.sub.6 alkyl;
X is selected from the group consisting of O, NH, CH.sub.2, CO, SO,
SO.sub.2 or S; Y represents a group selected from the following:
optionally substituted C.sub.1-C.sub.6 alkyl, --SR.sub.1,
--S(O)R.sub.1, --S(O).sub.2R.sub.1, --OR.sub.2, wherein R.sub.1 and
R.sub.2 are selected from optionally substituted: C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkenyl or C.sub.1-C.sub.4 alkynyl; the
optional substituent or substituents on R, R.sub.1, R.sub.2 and Y
being independently selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.6 alkyl, mono or di-C.sub.1-C.sub.6
alkylamino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.6 alkylaminocarbonyl, amino, carboxy,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6
alkynyloxy, C.sub.3-C.sub.12 cycloalkyl, C.sub.3-C.sub.18
heterocycloalkyl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, nitryl, aryl; all of which, except halogen, are
independently optionally substituted by one or more substituents,
selected from the group consisting of halogen, hydroxy,
C.sub.1-C.sub.6 alkyl, mono or di-C.sub.1-C.sub.6 alkylamino,
aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.6 alkylaminocarbonyl, amino, carboxy,
C.sub.1-C.sub.8 alkoxy, C.sub.3-C.sub.12 cycloalkyl,
C.sub.3-C.sub.18 heterocycloalkyl, C.sub.1-C.sub.8 alkylcarbonyl,
C.sub.1-C.sub.8 alkoxycarbonyl, nitryl, aryl.
[0003] Additionally the invention provides compounds of formula (I)
or a pharmaceutically acceptable salt or prodrug ester thereof:
##STR00003##
wherein R is halo or optionally substituted C.sub.1-C.sub.8 alkyl;
X is selected from the group consisting of O, NH, CH.sub.2, CO, SO,
SO.sub.2 or S; Y represents a group selected from the following:
optionally substituted C.sub.1-C.sub.8 alkyl, --SR.sub.1,
--S(O)R.sub.1, --S(O).sub.2R.sub.1, --OR.sub.1, wherein R.sub.1 is
C.sub.1-C.sub.4 alkyl; the optional substituent or substituents on
R and Y being independently selected from the group consisting of
halogen, hydroxy, C.sub.1-C.sub.8 alkyl, mono or di-C.sub.1-C.sub.8
alkylamino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.8 alkylaminocarbonyl, amino, carboxy,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.12 cycloalkyl,
C.sub.3-C.sub.18 heterocycloalkyl, C.sub.1-C.sub.8 alkylcarbonyl,
C.sub.1-C.sub.8 alkoxycarbonyl, nitryl, aryl; all of which, except
halogen, are independently optionally substituted by one or more
substituents, selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.8 alkyl, mono or di-C.sub.1-C.sub.8
alkylamino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.8 alkylaminocarbonyl, amino, carboxy,
C.sub.1-C.sub.8 alkoxy, C.sub.3-C.sub.12 cycloalkyl,
C.sub.3-C.sub.18 heterocycloalkyl, C.sub.1-C.sub.8 alkylcarbonyl,
C.sub.1-C.sub.8 alkoxycarbonyl, nitryl, aryl.
[0004] For the avoidance of doubt, the terms listed below are to be
understood to have the following meaning throughout the present
description and claims:
[0005] The term "lower", when referring to organic radicals or
compounds means a compound or radical with may be branched or
unbranched with up to and including 7 carbon atoms.
[0006] A lower alkyl group may be branched, unbranched or cyclic
and contains 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms.
Lower alkyl represents, for example: methyl, ethyl, propyl, butyl,
isopropyl, isobutyl, tertiary butyl or 2,2-dimethylpropyl.
[0007] A lower alkoxy group may be branched or unbranched and
contains 1 to 7 carbon atoms, preferably 1 to 6 carbon atoms. Lower
alkoxy represents, for example: methoxy, ethoxy, propoxy, butoxy,
isopropoxy, isobutoxy or tertiary butoxy. Lower alkoxy includes
cycloalkyloxy and cycloalkyl-lower alkyloxy.
[0008] A lower alkene, alkenyl or alkenoxy group is branched or
unbranched and contains 2 to 7 carbon atoms, preferably 1 to 4
carbon atoms and contains at least one carbon-carbon double bond.
Lower alkene, lower alkenyl or lower alkenyloxy represents for
example vinyl, prop-1-enyl, allyl, butenyl, isopropenyl or
isobutenyl and the oxy equivalents thereof.
[0009] A lower akyne or alkynyl group is branched or unbranched and
contains 2 to 7 carbon atoms, preferably 1 to 4 carbon atoms and
contains at least one carbon-carbon triple bond. Lower alkyne or
lower alkynyl or lower alkenyloxy represents for example ethynyl,
propynyl or propargyl.
[0010] In the present application, oxygen containing substituents,
e.g. alkoxy, alkenyloxy, alkynyloxy, carbonyl, etc. encompass their
sulphur containing homologues, e.g. thioalkyl, alkyl-thioalkyl,
thioalkenyl, alkenyl-thioalkyl, thioalkynyl, thiocarbonyl,
sulphone, sulphoxide etc.
[0011] Halo or halogen represents chloro, fluoro, bromo or
iodo.
[0012] Aryl represents carbocyclic aryl, heterocyclic aryl or
biaryl.
[0013] Carbocyclic aryl is an aromatic cyclic hydrocarbon
containing from 6 to 18 ring atoms. It can be monocyclic, bicyclic
or tricyclic, for example naphthyl, phenyl, or phenyl mono-, di- or
trisubstituted by one, two or three substituents.
[0014] Heterocyclic aryl is an aromatic monocyclic or bicyclic
hydrocarbon containing from 5 to 18 ring atoms one or more of which
are heteroatoms selected from O, N or S. Preferably there are one
or two heteroatoms. Heterocyclic aryl represents, for example:
pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl,
benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl,
furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl,
tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl,
benzimidazolyl. Heterocyclic aryl also includes such substituted
radicals.
[0015] Cycloalkyl represents a cyclic hydrocarbon containing from 3
to 12 ring atoms preferably from 3 to 6 ring atoms. Cycloalkyl
represents, for example: cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl. The cycloalkyl may optionally be substituted.
[0016] Heterocycloalkyl represents a mono-, di- or tricyclic
hydrocarbon which may be saturated or unsaturated and which
contains one or more, preferably one to three heteroatoms selected
from O, N or S. Preferably it contains between three and 18 ring
atoms. The term heterocycloalkyl is intended also to include
bridged heterocycloalkyl groups such as
3-hyroxy-8-aza-bicyclo[3.2.1]oct-8-yl.
[0017] Pharmaceutically acceptable salts include acid addition
salts with conventional acids, for example mineral acids, e.g.
hydrochloric acid, sulfuric or phosphoric acid, or organic acids,
for example aliphatic or aromatic carboxylic or sulfonic acids,
e.g. acetic, trifluoroacetic, propionic, succinic, glycolic,
lactic, malic, tartaric, citric, ascorbic, maleic, fumaric,
hydroxylmaleic, pyruvic, pamoic, methanesulfonic, toluenesulfonic,
naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; also
amino acids, such as arginine and lysine. For compounds of the
invention having acidic groups, for example a free carboxy group,
pharmaceutically acceptable salts also represent metal or ammonium
salts, such as alkali metal or alkaline earth metal salts, e.g.
sodium, potassium, magnesium or calcium salts, as well as ammonium
salts, which are formed with ammonia or suitable organic
amines.
[0018] The agents of the invention which comprise free hydroxyl
groups may also exist in the form of pharmaceutically acceptable,
physiologically cleavable esters, and as such are included within
the scope of the invention. Such pharmaceutically acceptable esters
are preferably prodrug ester derivatives, such being convertible by
solvolysis or cleavage under physiological conditions to the
corresponding agents of the invention which comprise free hydroxyl
groups. Suitable pharmaceutically acceptable prodrug esters are
those derived from a carboxylic acid, a carbonic acid monoester or
a carbamic acid, advantageously esters derived from an optionally
substituted lower alkanoic acid or an arylcarboxylic acid.
[0019] In preferred compounds of formula (I), X is CH.sub.2 or
O.
[0020] More preferably, X is CH.sub.2.
[0021] A second aspect of the invention provides a compound of
formula (I') or a pharmaceutically acceptable salt, or prodrug
ester thereof:
##STR00004##
wherein R' is halo or optionally substituted C.sub.1-C.sub.6 alkyl;
Y' represents a group selected from the following: C.sub.1-C.sub.6
alkyl, --SR.sub.1, --S(O)R.sub.1, --S(O).sub.2R.sub.1, --OR.sub.2,
wherein R.sub.1 and R.sub.2 are selected from optionally
substituted: C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or
C.sub.2-C.sub.4 alkynyl; the optional substituent or substituents
on R, R.sub.1 and R.sub.2 are independently selected from the group
consisting of halogen, hydroxy, C.sub.1-C.sub.6 alkyl, mono or
di-C.sub.1-C.sub.6 alkylamino, aminocarbonyl, sulfinyl, sulfonyl,
sulfanyl, mono or di-C.sub.1-C.sub.6 alkylaminocarbonyl, amino,
carboxy, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.12 cycloalkyl,
C.sub.3-C.sub.18 heterocycloalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, nitryl, aryl; all of which, except
halogen, are independently optionally substituted by one or more
substituents, selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.6 alkyl, mono or di-C.sub.1-C.sub.6
alkylamino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.6 r alkylaminocarbonyl, amino, carboxy,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.12 cycloalkyl,
C.sub.3-C.sub.18 heterocycloalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, nitryl, aryl.
[0022] Additionally in second aspect, the invention provides a
compound of formula (I') or a pharmaceutically acceptable salt, or
prodrug ester thereof:
##STR00005##
wherein R' is halo or optionally substituted C.sub.1-C.sub.6 alkyl;
Y' represents a group selected from the following: C.sub.1-C.sub.6
alkyl, --SR.sub.1, --S(O)R.sub.1, --S(O).sub.2R.sub.1, --OR.sub.1,
wherein R.sub.1 is C.sub.1-C.sub.4 alkyl;
[0023] The optional substituent or substituents on R are
independently selected from the group consisting of halogen,
hydroxy, C.sub.1-C.sub.6 alkyl, mono or di-C.sub.1-C.sub.6
alkylamino, aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.6 alkylaminocarbonyl, amino, carboxy, lower
alkoxy, C.sub.3-C.sub.12 cycloalkyl, C.sub.3-C.sub.18
heterocycloalkyl, C.sub.1-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6
alkoxycarbonyl, nitryl, aryl; all of which, except halogen, are
independently optionally substituted by one or more substituents,
selected from the group consisting of halogen, hydroxy,
C.sub.1-C.sub.6 alkyl, mono or di-C.sub.1-C.sub.6 alkylamino,
aminocarbonyl, sulfinyl, sulfonyl, sulfanyl, mono or
di-C.sub.1-C.sub.6 alkylaminocarbonyl, amino, carboxy,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.12 cycloalkyl,
C.sub.3-C.sub.18 heterocycloalkyl, C.sub.1-C.sub.6 alkylcarbonyl,
C.sub.1-C.sub.6 alkoxycarbonyl, nitryl, aryl.
[0024] With respect to the above described compounds of formula (I)
and formula (I') one or more of the following significances may
apply:
[0025] Preferably, Y is selected from: --OR.sub.2, --S(O)R.sub.1,
and --S(O).sub.2R.sub.1.
[0026] More preferably, Y is selected from --OR.sub.2 and
--SR.sub.1, yet more preferably --OR.sub.2.
[0027] Alternatively preferably, Y is selected from: --SR.sub.1,
--S(O)R.sub.1 and --S(O).sub.2R.sub.1.
[0028] R.sub.1 is preferably optionally substituted C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 alkynyl.
[0029] R.sub.1 is more preferably optionally substituted
C.sub.1-C.sub.4 alkyl.
[0030] More preferably, R.sub.1 or R.sub.2 is methyl.
[0031] Yet more preferably, Y is selected from: --SMe, --S(O)Me and
--S(O).sub.2Me.
[0032] Preferably R is halo or trifluoromethyl.
[0033] More preferably R is trifluoromethyl.
[0034] Preferred compounds of formula I are: [0035]
4-Bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methyls-
ulfanyl-pyridin-3-ylmethyl)-1H-benzoimidazole [0036]
2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methylsulfanyl--
pyridin-3-ylmethyl)-4-trifluoromethyl-1H-benzoimidazole [0037]
4-Bromo-2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-pyridin-3-ylmethyl)-7-
-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole [0038]
2-(4-Isopropyl-phenyl)-5-(2-methanesulfinyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole [0039]
2-(4-Isopropyl-phenyl)-5-(2-methanesulfonyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole [0040]
2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methoxy-pyridin-
-3-ylmethyl)-4-trifluoromethyl-1H-benzoimidazole [0041]
5-(2-Ethoxy-pyridin-3-ylmethyl)-2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-met-
hoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole [0042]
5-(2-Isopropoxy-pyridin-3-yl
methyl)-2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trifluorom-
ethyl-1H-benzoimidazole [0043]
2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-prop-2-ynyloxy--
pyridin-3-ylmethyl)-4-trifluoromethyl-1H-benzoimidazole [0044]
2-(4-Isopropyl-phenyl)-7-methoxy-5-[2-(2-methoxy-ethoxy)-pyridin-3-ylmeth-
yl]-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole [0045]
(2-{3-[2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trifluorome-
thyl-1H-benzoimidazole-5-ylmethyl]-pyridin-2-yloxy}-ethyl)-dimethylamine.
[0046] According to a third aspect of the invention there is
provided a pharmaceutical composition comprising a compound of
formula (I) in association with a pharmaceutically acceptable
excipient, diluent or carrier.
[0047] According to a fourth aspect of the invention there is
provided a compound of formula (I) for promoting the release of
parathyroid hormone.
[0048] It is now well established that controlled treatment of
patients with parathyroid hormone (PTH) and analogues and fragments
thereof can have a pronounced anabolic effect on bone formation.
Thus compounds which promote PTH release, such as the compounds of
the present invention may be used for preventing or treating
conditions of bone which are associated with increased calcium
depletion or resorption or in which stimulation of bone formation
and calcium fixation in the bone is desirable.
[0049] Thus in a fifth aspect the invention includes a method for
preventing or treating bone conditions which are associated with
increased calcium depletion or resorption or in which stimulation
of bone formation and calcium fixation in the bone is desirable in
which an effective amount of a compound of formula (I) as defined
above, or a pharmaceutically-acceptable and -cleavable ester, or
acid addition salt thereof is administered to a patient in need of
such treatment.
[0050] In a sixth aspect the invention provides a process for
preparation of a compound of formula (I) in free or salt form,
comprising:
(a) for compounds of formula (I) wherein R is optionally
substituted C.sub.1-C.sub.6 alkyl, introducing the optionally
substituted C.sub.1-C.sub.6 alkyl by reaction of a compound of
formula (XV) with a suitable organometallic reagent:
##STR00006##
(b) for compounds of formula (I) wherein R is halo, halogenation of
a compound of formula (X) using a suitable halogenating agent:
##STR00007##
(c) for compounds of formula (I) wherein Y is --SR.sub.1, reduction
of a compound of formula (XI) using a suitable reducing agent:
##STR00008##
(d) for compounds wherein Y is --S(O)R.sub.1 or
--S(O).sub.2R.sub.1, by oxidation of a compound of formula
(XII):
##STR00009##
(e) for compounds wherein Y is --OR.sub.2, or --SR.sub.1 by
ipso-substitution in the pyridine ring of a compound of formula
(XIII):
##STR00010##
[0051] In step (a), an example of a suitable reagent for
introduction of a methyl group at the R position would be
Me.sub.2CuLi.
[0052] In step (b), bromination, for example, of the compound of
formula (XV) may be carried out using bromine/acetic acid.
[0053] In step (c), 4-toluene-suphonic acid, sodium iodide in
acetonitrile may conveniently be used to effect the reduction of
the compound (XI).
[0054] In step (d), oxidation can be conveniently carried out for
example using hydrogen peroxide and acetic acid.
[0055] In step (e), selective Ipso-substitution in the pyridine
ring can be achieved with nucleophiles such as R.sub.2O.sup.- and
R.sub.1S.sup.-.
[0056] The abovementioned compounds of formula (XV), (XI), (XII)
and (XIII) may be prepared as outlined in the following
schemes:
[0057] Synthesis of compounds according to the invention of formula
(I) wherein X is --CH.sub.2-- is further illustrated by the
following Scheme 1:
##STR00011## ##STR00012##
[0058] Compounds of the invention wherein X is a group other than
--CH.sub.2-- may for example be prepared according to the following
Scheme 2:
##STR00013##
[0059] The compounds of formula I in free form may be converted
into salt forms in conventional manner and vice-versa.
[0060] The compounds of the invention can be recovered from the
reaction mixture and purified in conventional manner. Isomers, such
as enantiomers, may be obtained in conventional manner, e.g. by
fractional crystallization or asymmetric synthesis from
corresponding asymmetrically substituted, e.g. optically active
starting materials.
[0061] In a seventh aspect invention includes the use of a compound
of formula (I) in the manufacture of a medicament for preventing or
treating bone conditions which are associated with increased
calcium depletion or resorption or in which stimulation of bone
formation and calcium fixation in the bone is desirable.
[0062] The compounds of the invention may be used alone or in
combination with other suitable active agents. In an eighth aspect
of the invention, there is provided as pharmaceutical composition
comprising a compound of formula (I) and an additional active agent
selected from: a calcitonin or an analogue or derivative thereof, a
steroid hormone, a SERM (Selective Estrogen Receptor Modulator),
vitamin D or an analog thereof, a bisphosphonate, an RNKL
inhibitor, PTH, a PTH fragment or a PTH derivative, or a cathepsin
K inhibitor for simultaneous, separate or sequential use.
[0063] Agents of the invention may be prepared by processes
described below:
EXAMPLE 1
4-Bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methylsu-
lfanyl-pyridin-3-ylmethyl)-1H-benzoimidazole
##STR00014##
[0065] A mixture of 0.95 g (1.97 mmol)
2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methylsulfanyl--
pyridin-3-ylmethyl)-1H-benzoimidazole, 0.103 ml bromine 70 ml
acetic acid is stirred at room temperature for 1 h. After that the
reaction mixture is poured on water and extracted 3 times with
ethyl acetate. The organic layer is washed with 4N NaOH solution
(2.times.), water (3.times.) and brine (2.times.), dried
(MgSO.sub.4) and concentrated in vacuo. The residue is purified by
flash-chromatography on silica gel (hexanes/EtOAc 3:1=>EtOAc)
and recrystallisation from diethyl ether/hexane to give the title
compound as white crystals.
[0066] R.sub.t=2.26 min (Waters Symmetry C8, 2.1.times.50 mm,
detection 210-250 nM, 5% to 100% CH.sub.3CN in H.sub.2O in 2
min+0.1% TFA, flow rate 1.0 ml/min)
[0067] MS: 540 (M+1).sup.+ (.sup.79Br), 542 (M+1).sup.+
(.sup.81Br)
[0068] The starting materials can be prepared as follows:
a)
2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methylsulfany-
l-pyridin-3-ylmethyl)-1H-benzoimidazole
##STR00015##
[0070] A solution of 10.65 g (14.6 mmol) of
[2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5--
yl]-(2-methylsulfanyl-pyridin-3-yl)-methanol in 200 ml formic acid
is heated to reflux temperature. Over a period of ca. 24 h, 18.2 g
of zinc (powder) is added in small portions at reflux temperature.
After that the reaction mixture is cooled to room temperature,
poured on water and extracted 3 times with ethyl acetate. The
organic layer is washed with 4N NaOH solution (2.times.), water
(3.times.) and brine (2.times.), dried (MgSO.sub.4) and
concentrated in vacuo. The residue is purified by
flash-chromatography on silica gel (hexanes/EtOAc 2:1=>EtOAc)
followed by recrystallisation from diethyl ether/hexane to give the
title compound as colorless crystals.
b)
[2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol--
5-yl]-(2-methylsulfanyl-pyridin-3-yl)-methanol
##STR00016##
[0072] To a solution of 8.86 g (43.4 mmol)
3-bromo-2-methylsulfanyl-pyridine in 165 ml dry THF, n-BuLi (31 ml,
1.6M in hexane) is added slowly at -70.degree. C. Stirring is
continued at this temperature for 2 h, and a solution of 10 g (28.4
mmol)
2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5--
carbaldehyde (preparation of this compound is described in WO
2005/068433 A1) in 165 ml dry THF is added within 10 min. The
reaction mixture is allowed to reach room temperature and is poured
on water and extracted 3 times with ethyl acetate. The organic
layer is washed with water (3.times.) and brine (2.times.), dried
(Mg SO.sub.4) and concentrated in vacuo. The residue is purified by
flash-chromatography on silica gel (hexanes/EtOAc 1:1=>EtOAc) to
give the title compound as a yellow foam.
c) 3-Bromo-2-methylsulfanyl-pyridine
##STR00017##
[0074] A mixture of 10 g (50.9 mmol) 3-bromo-2-chloro-pyridine,
4.66 g (63.1 mmol) sodium methane-thiolate in 100 ml dry THF is
stirred at 60.degree. C. for 7 h. After that the reaction mixture
is cooled to room temperature and poured on water and extracted 3
times with ethyl acetate. The organic layer is washed with water
(1.times.) and brine (1.times.), dried (MgSO.sub.4) and
concentrated in vacuo to give the title compound as a colorless
oil.
EXAMPLE 2
2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methylsulfanyl-p-
yridin-3-ylmethyl)-4-trifluoromethyl-1H-benzoimidazole
##STR00018##
[0076] A mixture of 530 mg (0.7 mmol)
4-iodo-2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-pyridin-3-ylmethyl)-7--
methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole, 62.7 mg (0.351 mmol)
copper (I) iodide and 0.225 ml (1.76 mmol)
methyl-2,2-difluoro-2-(fluorosulfonyl)acetate (Aldrich 390755) in
15 ml dimethylformamide is stirred at 120.degree. C. for 4 h. After
that the reaction mixture is cooled to room temperature, poured on
water and extracted 3 times with ethyl acetate. The organic layer
is washed with water (3.times.) and brine (2.times.), dried
(MgSO.sub.4) and concentrated in vacuo. The residue is purified by
flash-chromatography on silica gel (hexanes/EtOAc 3:1=>2:1)
followed by recrystallisation from diethyl ether/hexane to give the
title compound as colorless crystals.
[0077] R.sub.t=2.38 min (Waters Symmetry C8, 2.1.times.50 mm,
detection 210-250 nM, 5% to 100% CH.sub.3CN in H.sub.2O in 2
min+0.1% TFA, flow rate 1.0 ml/min)
[0078] MS: 530 (M+1).sup.+
[0079] The starting materials can be prepared as follows:
a)
4-Iodo-2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-pyridin-3-ylmethyl)--
7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole
##STR00019##
[0081] A mixture of 2.38 g (5.0 mmol)
2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methylsulfanyl--
pyridin-3-ylmethyl)-1H-benzoimidazole, 1.3 g iodine and 1.6 g
silver sulfate in 50 ml acetic acid is stirred at 80.degree. C. for
4 h, where another 1.3 g iodine and 1.6 g silver sulfate are added
(as one equivalent of reagents is used to oxidize the sulfur,
addition of another equivalent is necessary). Stirring is continued
for 3 h. After that the reaction mixture is cooled to room
temperature, poured on water and extracted 3 times with ethyl
acetate. The organic layer is washed with 4N NaOH solution, water
(3.times.) and brine (2.times.), dried (MgSO.sub.4) and
concentrated in vacuo. The residue is recrystallised from
dichloromethane/diethyl ether to give the title compound as
off-white crystals.
EXAMPLE 3
2-(4-Isopropyl-phenyl)-5-(2-methanesulfinyl-pyridin-3-ylmethyl)-7-methoxy--
1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole
##STR00020##
[0083] A mixture of 30 mg (0.057 mmol)
2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methylsulfanyl--
pyridin-3-ylmethyl)-4-trifluoromethyl-1H-benzoimidazole (example 2)
and 6.4 microliter hydrogen peroxide/water solution in 1 ml acetic
acid are stirred at room temperature for 3 h. After that the
reaction mixture is diluted with ethyl acetate and washed with 4N
NaOH solution (1.times.), water (1.times.) and NaHSO.sub.3 solution
(1.times.), dried (MgSO.sub.4) and concentrated in vacuo to give
the title compound as a colorless oil.
[0084] R.sub.t=2.11 min (Waters Symmetry C8, 2.1.times.50 mm,
detection 210-250 nM, 5% to 100% CH.sub.3CN in H.sub.2O in 2
min+0.1% TFA, flow rate 1.0 ml/min)
[0085] MS: 546 (M+1).sup.+
EXAMPLE 4
2-(4-Isopropyl-phenyl)-5-(2-methanesulfonyl-pyridin-3-ylmethyl)-7-methoxy--
1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole
##STR00021##
[0087] A mixture of 16 mg (0.029 mmol)
2-(4-isopropyl-phenyl)-5-(2-methanesulfinyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole (example
3) and 6.0 microliter hydrogen peroxide/water solution in 1 ml
acetic acid are stirred at room temperature for 3 h. After that the
reaction mixture is diluted with ethyl acetate and washed with 4N
NaOH solution (1.times.), water (1.times.) and NaHSO3 solution
(1.times.), dried (MgSO.sub.4) and concentrated in vacuo to give
the title compound as a colorless oil.
[0088] R.sub.t=2.27 min (Waters Symmetry C8, 2.1.times.50 mm,
detection 210-250 nM, 5% to 100% CH.sub.3CN in H.sub.2O in 2
min+0.1% TFA, flow rate 1.0 ml/min)
[0089] MS: 562 (M+1).sup.+
EXAMPLE 5
4-Bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methylsu-
lfinyl-pyridin-3-ylmethyl)-1H-benzoimidazole
##STR00022##
[0091] The title compound can be prepared from
4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methyls-
ulfanyl-pyridin-3-ylmethyl)-1H-benzoimidazole using the same
methodology as described for the preparation of example 3.
[0092] R.sub.t=2.04 min (Waters Symmetry C8, 2.1.times.50 mm,
detection 210-250 nM, 5% to 100% CH.sub.3CN in H.sub.2O in 2
min+0.1% TFA, flow rate 1.0 ml/min)
[0093] MS: 556 (M+1).sup.+ (.sup.79Br), 558 (M+1).sup.+
(.sup.81Br)
EXAMPLE 6
2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-methoxy-pyridin--
3-ylmethyl)-4-trifluoromethyl-1H-benzoimidazole
##STR00023##
[0095] R.sub.t=2.11 min (Waters Symmetry C8, 2.1.times.50 mm,
detection 210-250 nM, 5% to 100% CH.sub.3CN in H.sub.2O in 2
min+0.1% TFA, flow rate 1.0 ml/min)
[0096] MS: 514 (M+1).sup.+
[0097] The title compound is prepared using the same methodology as
described for the preparation of example 2 from
3-bromo-2-methoxy-pyridine instead of
3-bromo-2-methylsulfanyl-pyridine.
Alternative Procedure:
[0098] R.sub.t=2.39 min (Phenomenex Luna C8, 2.times.50 mm, 3
.mu.m, detection 190-270 nm, Solvent: A:
CH.sub.3CN/H.sub.2O/TFA=95/5/0.1, B: CH.sub.3CN/TFA=100/0.1,
Gradient: starting with 5% B and coming up to 95% B within 2 min
then 95% B for 1 min and going back to 5% B within 0.3 min, flow
rate 1.0 ml/min)
[0099] A solution of
2-(4-isopropyl-phenyl)-5-(2-methanesulfonyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole (100 mg,
0.177 mmol, for preparation see Example 4) in dioxane (2 ml) is
treated with sodium methylate (201 mg, 3.54 mmol). A small amount
of MeOH (1 ml) needs to be added in order to obtain a solution. The
reaction mixture is stirred at 50.degree. C. for 60 hrs. Work-up is
done by the addition of water (10 ml) followed by stirring for 2
hrs at room temperature resulting in the formation of white
crystals. They are filtered off and washed with water to give pure
product.
EXAMPLE 7
5-(2-Ethoxy-pyridin-3-ylmethyl)-2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-meth-
oxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole
##STR00024##
[0101] R.sub.t=2.45 min (Phenomenex Luna C8, 2.times.50 mm, 3
.mu.m, detection 190-270 nm, Solvent: A:
CH.sub.3CN/H.sub.2O/TFA=95/5/0.1, B: CH.sub.3CN/TFA=100/0.1,
Gradient: starting with 5% B and coming up to 95% B within 2 min
then 95% B for 1 min and going back to 5% B within 0.3 min, flow
rate 1.0 ml/min)
[0102] MS: 528 (M+1).sup.+
[0103] A suspension of
2-(4-isopropyl-phenyl)-5-(2-methanesulfonyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole (100 mg,
0.177 mmol, for preparation see Example 4) in dioxane (1.30 ml) is
mixed with a solution of sodium ethylate in ethanol (21%, 1.3 ml,
3.5 mmol). The resulting solution is stirred overnight at
50.degree. C. The reaction mixture is then cooled to room
temperature, mixed with aqueous NaHCO.sub.3 solution (saturated)
and extracted with ethyl acetate (3.times.). The combined organic
layers are washed with water and brine, dried over Na.sub.2SO.sub.4
and the solvent removed under reduced pressure. The crude product
is purified by chromatography (silica, solvent: hexane/ethyl
acetate 75/25) to yield the product in form of a pale yellow
powder.
EXAMPLE 8
5-(2-Isopropoxy-pyridin-3-ylmethyl)-2-(4-Isopropyl-phenyl)-7-methoxy-1-(2--
methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole
##STR00025##
[0105] R.sub.t=2.50 min (Phenomenex Luna C8, 2.times.50 mm, 3
.mu.m, detection 190-270 nm, Solvent: A:
CH.sub.3CN/H.sub.2O/TFA=95/5/0.1, B: CH.sub.3CN/TFA=100/0.1,
Gradient: starting with 5% B and coming up to 95% B within 2 min
then 95% B for 1 min and going back to 5% B within 0.3 min, flow
rate 1.0 ml/min)
[0106] MS: 542.1 (M+1).sup.+, 1083.3 (2M+1).sup.+
[0107] A suspension of
2-(4-isopropyl-phenyl)-5-(2-methanesulfonyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole (100 mg,
0.177 mmol, for preparation see Example 4) n dioxane (1.30 ml) is
mixed with isopropyl alcohol (208 .mu.l, 3.54 mmol). NaH (60% in
mineral oil, 3.9 mmol) is added and the resulting reaction mixture
is stirred at 50.degree. C. for several days until more than 90% of
conversion to the desired product can be determined by LC/MS
analysis. Then, saturated aqueous NaHCO.sub.3 solution (50 ml) is
added and the resulting mixture is extracted with ethyl acetate
(3.times.). The combined organic phases are washed with water and
brine, dried over Na.sub.2SO.sub.4 and the solvent removed under
reduced pressure. The crude product is purified by column
chromatography (ethyl acetate/hexanes) to yield pure material as a
colorless oil.
EXAMPLE 9
2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-5-(2-prop-2-ynyloxy-p-
yridin-3-ylmethyl)-4-trifluoromethyl-1H-benzoimidazole
##STR00026##
[0109] R.sub.t=2.44 min (Phenomenex Luna C8, 2.times.50 mm, 3
.mu.m, detection 190-270 nm, Solvent: A:
CH.sub.3CN/H.sub.2O/TFA=95/5/0.1, B: CH.sub.3CN/TFA=100/0.1,
Gradient: starting with 5% B and coming up to 95% B within 2 min
then 95% B for 1 min and going back to 5% B within 0.3 min, flow
rate 1.0 ml/min)
[0110] MS: 538.1 (M+1).sup.+, 1075.3 (2M+1).sup.+
[0111] A suspension of
2-(4-isopropyl-phenyl)-5-(2-methanesulfonyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole (100 mg,
0.177 mmol, for preparation see Example 4) in dioxane (1.30 ml) is
mixed with propargyl alcohol (208 .mu.l, 3.54 mmol). NaH (60% in
mineral oil, 156 mg, 3.9 mmol) is added and the resulting solution
stirred overnight at 50.degree. C., after which additional NaH (60%
in mineral oil, 20 mg) is added. Stirring is continued at
50.degree. C. until LC/MS analysis shows approx. 95% conversion to
the desired product (16 hrs). Then water (5 ml) is added to the
mixture upon which the product starts to crystallize. The material
was filtered off and washed with water to give pure white
crystals.
EXAMPLE 10
2-(4-Isopropyl-phenyl)-7-methoxy-5-[2-(2-methoxy-ethoxy)-pyridin-3-ylmethy-
l]-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole
##STR00027##
[0113] R.sub.t=2.18 min (Phenomenex Luna C8, 2.times.50 mm, 3
.mu.m, detection 190-270 nm, Solvent: A:
CH.sub.3CN/H.sub.2O/TFA=95/5/0.1, B: CH.sub.3CN/TFA=100/0.1,
Gradient: starting with 5% B and coming up to 95% B within 2 min
then 95% B for 1 min and going back to 5% B within 0.3 min, flow
rate 1.0 ml/min)
[0114] MS: 558 (M+1).sup.+
[0115] A solution of
2-(4-isopropyl-phenyl)-5-(2-methanesulfonyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole (100 mg,
0.177 mmol, for preparation see Example 4) in dioxane (2 ml) is
mixed with 2-methoxyethanol (281 .mu.l, 3.56 mmol). NaH (60% in
mineral oil, 14.2 mg, 0.36 mmol) is added and the resulting
reaction mixture is stirred for 60 hrs at 60.degree. C. The
reaction mixture is quenched with saturated aqueous NaHCO.sub.3
solution and extracted with ethyl acetate (3.times.). The combined
organic layers are washed with water and brine, dried over
Na.sub.2SO.sub.4 and the solvent removed under reduced pressure.
The crude product is purified by chromatography (ethyl
acetate/hexanes) to give a pale yellow gluey substance.
EXAMPLE 11
(2-{3-[2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trifluoromet-
hyl-1H-benzoimidazole-5-ylmethyl]-pyridin-2-yloxy}-ethyl)-dimethylamine
##STR00028##
[0117] R.sub.t=1.87 min (Phenomenex Luna C8, 2.times.50 mm, 3
.mu.m, detection 190-270 nm, Solvent: A:
CH.sub.3CN/H.sub.2O/TFA=95/5/0.1, B: CH.sub.3CN/TFA=100/0.1,
Gradient: starting with 5% B and coming up to 95% B within 2 min
then 95% B for 1 min and going back to 5% B within 0.3 min, flow
rate 1.0 ml/min)
[0118] MS: 571 (M+1).sup.+
[0119] A solution of
2-(4-isopropyl-phenyl)-5-(2-methanesulfonyl-pyridin-3-ylmethyl)-7-methoxy-
-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazole (100 mg,
0.177 mmol, for preparation see Example 4) in dioxane (2 ml) is
mixed with 2-dimethylaminoethanol (415 .mu.l, 3.56 mmol). NaH (60%
in mineral oil, 14.2 mg, 0.36 mmol) is added and the resulting
reaction mixture stirred for 6p hrs at 60.degree. C. The reaction
mixture is quenched with saturated aqueous NaHCO.sub.3 solution and
extracted with ethyl acetate (3.times.). The combined organic
layers are washed with water and brine, dried over Na.sub.2SO.sub.4
and the solvent removed under reduced pressure. The crude product
is purified by silicagel chromatography (DCM/MeOH) to give a pale
yellow gluey substance.
[0120] The Agents of the Invention, as defined above, e.g., of
formula (I), particularly as exemplified, in free or
pharmaceutically acceptable acid addition salt form, exhibit
pharmacological activity and are useful as pharmaceuticals, e.g.
for therapy, in the treatment of diseases and conditions as
hereinafter set forth.
Inositol Phosphate Formation Assay:
[0121] To determine antagonistic activity at the human parathyroid
calcium-sensing receptor (PCaR), compounds are tested in functional
assays measuring the inhibition of calcium-induced inositol
phosphate formation in CCL39 fibroblasts stably transfected with
human PCaR.
[0122] Cells are seeded into 24 well plates and grown to
confluence. Cultures are then labelled with [.sup.3H]inositol (74
Mbq/ml) in serum-free medium for 24 h. After labelling, cells are
washed once with a modified Hepes-buffered salt solution (mHBS: 130
mM NaCl, 5.4 mM KCl, 0.5 mM CaCl.sub.2, 0.9 mM MgSO.sub.4, 10 mM
glucose, 20 mM HEPES, pH 7.4) and incubated with mHBS at 37.degree.
C. in the presence of 20 mM LiCl to block inositol monophosphatase
activity. Test compounds are added 3 minutes before stimulating
PCaR with 5.5 mM calcium and incubations continued for further 20
min. Thereafter, cells are extracted with 10 mM ice-cold formic
acid and inositol phosphates formed are determined using anion
exchange chromatography and liquid scintillation counting.
Assay for Intracellular Free Calcium:
[0123] An alternative method to determine antagonism at the PCaR
consists in measuring the inhibition of intracellular calcium
transients stimulated by extracellular calcium. CCL39 fibroblasts
stably transfected with human PCaR are seeded at 40'000 cells/well
into 96-well Viewplates and incubated for 24 hours. Medium is then
removed and replaced with fresh medium containing 2 .mu.M Fluo-3 AM
(Molecular Probes, Leiden, The Netherlands), In routine
experiments, cells are incubated at 37.degree. C., 5% CO.sub.2 for
1 h. Afterwards, plates are washed twice with mHBS and wells are
refilled with 100 .mu.l mHBS containing the test compounds.
Incubation is continued at room temperature for 15 minutes. To
record changes of intracellular free calcium, plates are
transferred to fluorescence-imaging plate reader (Molecular
Devices, Sunnyvale, Calif., USA). A baseline consisting in 5
measurements of 0.4 seconds each (laser excitation 488 nm) is
recorded. Cells are then stimulated with calcium (2.5 mM final),
and fluorescence changes recorded over a period of 3 minutes.
[0124] When measured in the above assays, Agents of the Invention
typically have IC.sub.50s in the range from about 1000 nM down to
about 10 nM or less. To illustrate the activity of the agents of
the invention, the following examples are provided based on the
above described assay:
TABLE-US-00001 Example no. IC.sub.50 [nM] 1 3.4 3 2.6 8 3.2 9
1.8
[0125] It is now well established that controlled treatment of
patients with parathyroid hormone (PTH) and analogues and fragments
thereof can have a pronounced anabolic effect on bone formation.
Thus compounds which promote PTH release, such as the Agents of the
Invention may be used for preventing or treating conditions of bone
which are associated with increased calcium depletion or resorption
or in which stimulation of bone formation and calcium fixation in
the bone is desirable.
[0126] Agents of the Invention are accordingly indicated for
preventing or treating all bone conditions which are associated
with increased calcium depletion or resorption or in which
stimulation of bone formation and calcium fixation in the bone is
desirable, e.g. osteoporosis of various genesis (e.g. juvenile,
menopausal, post-menopausal, post-traumatic, caused by old age or
by cortico-steroid therapy or inactivity), fractures, osteopathy,
including acute and chronic states associated with skeletal
demineralisation, osteo-malacia, periodontal bone loss or bone loss
due to arthritis or osteoarthritis or for treating
hypoparathyroidism.
[0127] Further diseases and disorders which might be prevented or
treated include e.g. seizures, stroke, head trauma, spinal cord
injury, hypoxia-induced nerve cell damage such as in cardiac arrest
or neonatal distress, epilepsy, neurodegenerative diseases such as
Alzheimer's disease, Huntington's disease and Parkinson's disease,
dementia, muscle tension, depression, anxiety, panic disorder,
obsessive-compulsive disorder, post-traumatic stress disorder,
schizophrenia, neuroleptic malignant syndrome, congestive heart
failure; hypertension; gut motility disorders such as diarrhea, and
spastic colon and dermatological disorders, e.g. in tissue healing,
for example burns, ulcerations and wounds.
[0128] The Agents of the Invention are particularly indicated for
preventing or treating osteoporosis of various genesis.
[0129] For all the above uses, an indicated daily dosage is in the
range from about 0.03 to about 1000 mg, preferably 0.03 to 200 mg,
more preferably 0.03 to 30, yet more preferably 0.1 to 10 mg of a
compound of the invention. Agents of the Invention may be
administered twice a day or up to twice a week.
[0130] The Agents of the Invention may be administered in free form
or in pharmaceutically acceptable salt form. Such salts may be
prepared in conventional manner and exhibit the same order of
activity as the free compounds. The present invention also provides
a pharmaceutical composition comprising an Agent of the Invention
in free base form or in pharmaceutically acceptable salt form in
association with a pharmaceutically acceptable diluent or carrier.
Such compositions may be formulated in conventional manner. The
Agents of the Invention may be administered by any conventional
route, for example parenterally e.g. in the form of injectable
solutions or suspensions, enterally, e.g. orally, for example in
the form of tablets or capsules or in a transdermal, nasal or a
suppository form.
[0131] In accordance with the foregoing the present invention
further provides:
a) an Agent of the Invention or a pharmaceutically acceptable salt
thereof for use as a pharmaceutical; b) a method for preventing or
treating above mentioned disorders and diseases in a subject in
need of such treatment, which method comprises administering to
said subject an effective amount of an Agent of the Invention or a
pharmaceutically acceptable salt thereof; c) an Agent of the
Invention or a pharmaceutically acceptable salt thereof for use in
the preparation of a pharmaceutical composition e.g. for use in the
method as in b) above.
[0132] According to a further embodiment of the invention, the
Agents of the Invention may be employed as adjunct or adjuvant to
other therapy, e.g. a therapy using a bone resorption inhibitor or
a bone formation promoter, for example as in osteoporosis therapy
or in cancer therapy, in particular a therapy employing calcium, a
calcitonin or an analogue or derivative thereof, e.g. salmon, eel
or human calcitonin, a steroid hormone, e.g. an estrogen, a partial
estrogen agonist or estrogen-gestagen combination, a SERM
(Selective Estrogen Receptor Modulator) e.g. raloxifene,
lasofoxifene, bazedoxifene, arzoxifene, TSE-424, FC1271, Tibolone
(Livial.RTM.), vitamin D or an analog thereof, a bisphosphonate,
e.g. an injectable like zoledronic acid or ibandronate, an RNKL
inhibitor, e.g. denosumab, PTH, a PTH fragment or a PTH derivative
e.g. PTH (1-84), PTH (1-34), PTH (1-36), PTH (1-38), PTH
(1-31)NH.sub.2 or PTS 893, or a cathepsin K inhibitor, e.g.
balicatib.
[0133] When the Agents of the Invention are administered in
conjunction with, e.g. as an adjuvant to bone resorption inhibition
therapy, dosages for the co-administered inhibitor will of course
vary depending on the type of inhibitor drug employed, e.g. whether
it is a steroid or a calcitonin, on the condition to be treated,
whether it is a curative or preventive therapy, on the regimen and
so forth. Administration may be by any convenient route, e.g.
parenterally, orally and may be administered simultaneously,
separately or sequentially or at differently timed intervals.
* * * * *